【作者】 余晓云；

【导师】 侯晓华；

【作者基本信息】 华中科技大学 ， 内科学， 2009， 博士

【摘要】 第一部分顺铂和阿朴吗啡对犬呕吐症状和胃慢波的影响目的观察分别给予顺铂(Cisplatin)和阿朴吗啡(Apomorphine)后犬呕吐等消化不良症状的程度及其对胃肌电活动的影响。方法7只比格犬分别植入4对胃浆膜电极，并进行2部分实验。1．顺铂组：每只犬分别记录给药前20min胃电基线水平及消化不良症状后，经静脉持续注射顺铂溶液(1.5 mg／kg溶于250 ml生理盐水)1h，并自实验开始持续记录胃肌电活动及动物症状共约6 h。2．阿朴吗啡组：将阿朴吗啡0.1mg／kg溶于生理盐水中配成0.01 mg／ml溶液，记录给药前胃电图基线水平15 min后皮下注射阿朴吗啡，以15 min为时间段，连续记录胃电活动和动物症状45 min。结果1．顺铂和阿朴吗啡均能诱导犬恶心呕吐等消化不良症状。(1)比格犬静脉注射顺铂期间及之后的约2.5 h内症状较轻微，其症状评分分别为1.86±0.26和7.43±1.39；在给药停止后约3 h动物开始出现频繁舔舌、哈欠、闭眼、急促呼吸等恶心样症状及呕吐，呕吐期间症状评分为20.29±0.94，较给药开始时明显增加(P＜0.01)，平均呕吐次数为5.0±1.86次；呕吐停止后动物症状逐渐恢复，症状评分为2.86±0.4。(2)阿朴吗啡组动物呕吐次数为5.29±0.87次，呕吐期间症状评分为12±0.95，之后逐渐降低至2.00±0.62。2．通过胃电记录发现，顺铂组给药前正常胃慢波占(89.7±3.11)％，而呕吐期间正常胃慢波为(67.0±5.1)％(P＜0.001)，并且胃电过速和胃电过缓发生的百分比明显高于给药前水平(P=0.008和P=0.026)，此外，顺铂还能减少胃慢波的主功率。在给药前胃慢波主功率为(1.5±2.1)dB，在呕吐期间主功率减低至(-3.3±0.7) dB (P=0.038)。阿朴吗啡组在呕吐期间其正常胃慢波百分比则从给药前的(96.51±1.14)％降低至(53.07±6.72)％，并且该时间段胃电过速和胃电过缓发生的比例同样高于给药前水平(P=0.011和P=0.015)。而胃电主频率及主功率并无明显变化。结论顺铂和阿朴吗啡均能诱导犬呕吐和恶心样症状，并引起胃电紊乱。第二部分胃电刺激对阿朴吗啡和顺铂诱导的犬呕吐症状的影响目的研究阿朴吗啡(Apomorphine，APO)和顺铂(Cisplatin，DDP)对胃肌电活动的影响，并探讨胃电刺激(Gastric Electrical Stimulation，GES)对化疗药物引起的犬呕吐和消化不良症状的治疗效应。方法7只比格犬分别植入4对胃浆膜电极，每只犬分别进行2部分实验。1．阿朴吗啡组：(1)对照组(APO-C)：记录给药前胃电图基线水平15 min后皮下注射阿朴吗啡(0.1 mg／kg)，以15 min为时间段，连续记录胃电活动和动物症状60 min。(2)阿朴吗啡+电刺激组(APO+GES)：每只犬均进行4次实验。每次实验给药及记录方法同对照组，但在阿朴吗啡给药的同时经近端胃体电极分别给予不同参数胃电刺激，并持续至实验结束，根据4组参数的结果选出一组最佳参数，并用于顺铂部分的实验。2．顺铂组：(1)DDP对照组在记录20 min胃慢波基线及动物症状后，持续静脉注射DDP溶液(1.5 mg／kg溶于250 ml生理盐水)1 h，在给药期间及给药后的5 h内持续记录胃电活动及动物症状，并计算症状评分；(2)DDP+GES组除了在给药同时开始经近端胃体部电极持续给予GES外，其给药方式、剂量及胃电和症状记录同各自的对照组。结果1．阿朴吗啡和顺铂均能诱导犬恶心呕吐等症状及胃电紊乱。(1)APO对照组动物平均呕吐次数为5.29±0.87次，总症状评分为20.57±1.81。呕吐期间其正常胃慢波仅为(53.07±6.72)％，并且该时间段胃电过速和胃电过缓发生的比例同样高于基线水平(P=0.011和P=0.015)。(2)DDP对照组动物均出现频繁呕吐，平均呕吐次数为5.5±1.2次，总症状评分为31.83±2.75。通过胃电记录发现，给药前基线水平正常胃慢波占(96.5±1.14)％，而呕吐期间正常胃慢波降低至(69.61±5.81)％(P=0.003vs．baseline)，并且胃电过速和胃电过缓发生的百分比均明显高于给药前水平(P=0.02和P=0.031)。2．胃电刺激能减轻阿朴吗啡和顺铂诱导的呕吐和消化不良症状。(1)4组胃电刺激参数中GES4能显著改善APO诱导的呕吐反应。APO+GES4组动物呕吐次数明显减少(3.71±0.61，P=0.025 vs．APO对照组)，其症状评分降低至15.86±1.82(P=0.033 vs．对照组)。(2)DDP+GES组动物的症状评分也较对照组明显降低(24.5±1.45，P=0.028)，并且呕吐次数也明显减少(3.67±0.8，P=0.028)。但胃电刺激对两种药物引起的胃电紊乱并无明显影响。结论阿朴吗啡和顺铂能诱导犬呕吐和胃电紊乱。高频串脉冲胃电刺激能明显减轻药物引起的呕吐和消化不良症状，但对胃电变化无明显影响。第三部分胃电刺激的脑功能磁共振研究目的研究不同参数的胃电刺激对犬中枢神经系统神经元活性的影响，初步探讨胃电刺激的中枢作用机制。方法5只比格犬只分别植入4对胃浆膜电极。每只犬于麻醉后分别给予3种不同参数的胃电刺激(串脉冲、短脉冲和长脉冲)，并进行fMRI扫描。fMRI扫描共分2部分：扫描犬静息状态下脑血流情况(5 min)，随即持续给予不同参数的胃电刺激15min，比较胃电刺激前后脑血流变化。结果串脉冲组在给予胃电刺激后脑血流信号明显增强的区域主要为海马、杏仁核、额叶、枕叶及脑干。部分犬在后丘脑(外侧膝状体、内侧膝状体)、腹侧丘脑和嗅回区域也可检测到血流信号的增强。短脉冲与长脉冲组血流信号明显增强的区域主要为脑干、额叶和枕叶，而海马和／或杏仁核区域均未见活化信号(P=0.038 vs．串脉冲组，卡方检验)。此外，短脉冲组在小脑区域可见明显的活化信号(P=0.039 vs．串脉冲组)，而长脉冲组小脑区域活化信号较弱。结论3种参数的胃电刺激均可引起脑干区域活化，提示脑干核团可能是3种刺激参数共同的作用通路。串脉冲和短脉冲刺激还可引起与内脏感觉相关的中枢区域活化，长脉冲刺激则对内脏感觉相关区域无明显作用。更多还原

【Abstract】 Part 1 Drug-Induced Gastric Dysrhythmia and Emesis in DogsAims: The aims of this study were to investigate the effects of Cisplatin (DDP) andApomorphine (APO) on gastric myoelectrical activity in dogs.Methods: Seven female dogs chronically implanted with four pairs of electrodes ongastric serosa were used in a two-session study.Intravenous infusion of DDP (1.5 mg / kg)was given for 1h in DDP session.APO (0.1 mg/kg) was injected subcutaneously in APOsession.Gastric slow waves and emesis as well as behaviors suggestive of nausea wererecorded in each session.Results: 1.DDP and APO induced emesis and behaviors suggestive of nausea.(1) TheEmesis frequency was 5.5±1.2 in DDP session.The symptoms were slight in the period ofinfusion and before vomiting, and the symptoms scores were 1.86±0.26 and 7.43±1.39.Allthe dogs presented more frequent nausea-like responses such as licking tongue, belchingand chasma, and multiple vomiting.The behavioral score in the vomiting period was20.3±0.9, which was higher than that in other periods (each P < 0.01).(2) In the APOsession, the vomiting frequency was 5.29±0.87.All the dogs presented more frequentnausea-like responses within 15min after APO infusion, and the symptoms score in thisperiod was 12±0.95 (P < 0.001 vs.baseline).Within 30 - 45 min after APO infusion, thesymptoms score decreased to 2.00±0.62 (P=0.085 vs.baseline).2.DDP and APO inducedgastric dysrhythmia.(1) In DDP session, the percentage of normal slow waves decreasedsignificantly during the 2.5 h before vomiting ((77.7±5.6) %, P=0.01 ) and the period ofvomiting ((69.8±4.5) %, P < 0.001) compared with baseline.In addition, the dominantpower of gastric slow wave decreased from (1.5±2.1) dB in baseline to (-3.3±0.7) dB in the period of vomiting (P=0.038).(2) It also induced bradygastria and tachygastria in thefirst 15min after APO infusion (P=0.015 and P=0.011 vs.baseline).The normal slowwave was (53.07±6.72) % (P=0.001 vs.baseline).Conclusion: Cisplatin and Apomorphine induced emesis and nausea-like responses,which caused gastric dysrhythmia. Part 2 Effect of Gastric Electrical Stimulationon Drug-Induced EmesisObjective The aims of this study were to investigate the effects of Cisplatin (DDP)and Apomorphine (APO) on gastric myoelectrical activity and the roles of GES in treatingdrug-induced emesis in dogs.Methods Seven female dogs chronically implanted with four pairs of electrodes ongastric serosa were used in a two -session study.1.APO (0.1 mg/kg) was injectedsubcutaneously in APO-control session and APO + GES session.4 kinds of GES wereapplied on the proximal pair of gastric electrodes from drugs infusion in APO-GESsessions.Select the best parameter according to the result and apply it to the DDP-GESsession.2.Intravenous infusion of DDP (1.5 mg/kg) was given for 1h in DDP -controlsession and DDP + GES session.It lasted 6 h in GES session and 1 h in APO + GESsession.Gastric slow waves and animal behaviors were recorded in each session.Results 1.Cisplatin and Apomorphine induced emesis and behaviors suggestive ofnausea, and gastric dysrhythmia.(1) The total number of emesis was 5.5±1.2 in DDP-control session, and thc total symptom score was 31.83±2.75.The gastric slow waveshowed both bradygastria and tachygastria during the period of emesis (P=0.031 and P=0.02 vs.baseline).The percentage of normal slow wave was 69.61±5.81% during thisperiod (P=0.003 vs.baseline).(2) In the APO -control session, the total number of emesiswas 5.29±0.87 and the symptom score was 20.57±1.81.It also induced bradygastria andtachygastria in the first 15 min after APO infusion (P=0.015 and 0.011 vs.baseline).Thenormal slow wave was (53.07±6.72) % (P=0.001 vs.baseline).2.GES reduced emesisand the animal behavioral score suggestive of nausea compared with control sessions.(1)Among these 4 parameters, GES4 can reduced the vomiting time significantly.The totalsymptoms score in APO + GES4 session decreased (15.86±1.82, P=0.033 vs.controlsession).GES4 can also decrease the vomiting time in this session (3.71±0.61, P=0.025vs.control session).(2) The total symptom score in DDP + GES session decreased to 24.5±1.45 (P=0.028 vs.control session), and the vomiting times was 3.67±0.8(P=0.028vs.control session).However, GES had no effects on gastric dysrhythmia.Conclusion APO and DDP induced emesis and gastric dysrhythmia.GES with trainsof short pulses relieves drug -induced emetic responses but has no effects on dysrhythmia. Part 3 Functional Magnetic Resonance Imaging on GastricElectrical Stimulation in DogsObjective To investigate the effect of gastric electrical stimulation (GES) withdifferent parameters on the neuronal activity in central nervous system, and find thepossible mechanism of GES.Methods Five female dogs chronically implanted with four pairs of electrodes ongastric serosa were used in a three - part study.Each dog was anesthetized and given 3kinds of GES (trains of short pulse, shout pulse and long pulse) for 15min after baseline (5min) respectively.The location of cerebral activation induced by GES was investigated byfMRI.Result fMRI showed that GES with trains of short pulse induced BOLD - signalincreased in brainstem, frontal lobe, occipital lobe, and limbic brain areas, including theamygdale and hippocampus, which were considered to be correlated with chemoreceptortrigger zone and visceral sensation.GES with short pulse induced signal increased inbrainstem, occipital lobe, frontal lobe and cerebellum, but GES with long pulse only causedneuron activity in brainstem, frontal lobe and occipital lobe.Conclusion Each of these GES caused BOLD - signal increased in brainstem, whichindicate that the brainstem may be the same original pathway in the effect of GES oncentral nervous system.GES with short pulse and trains of short pulse also caused neuronalactivity in the areas correlated with visceral sensation.However, GES with long pulse hadno effect on the visceral sensation correlated areas.更多还原